The present invention is directed to compounds defined by the formula (X) below, including isopropyl 3S-amino-2R-hydroxy-4-phenylbutyrate which is also specifically depicted by the formula (I) below when R is C.sub.6 H.sub.5. The latter is converted by a conventional hydrogenation process to isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate (of the formula (I) below when R is cyclohexyl). The present invention is also directed to various steps of the multistep process used in the preparation of the compounds of the formula (I) from R-malic acid. The compounds of the formula (I) when R is (CH.sub.3).sub.2 CH or cyclohexyl are of known utility in the synthesis of various renin inhibiting compounds (see, for example, Johnson, J. Med. Chem., vol. 25, pp. 605-610, 1982; Rich et al., J. Org. Chem., vol. 45, pp. 2288-2290, 1980; Tobe et al., Agric. Biol. Chem., vol. 43, pp. 591-596, 1979; Nishizawa et al., J. Med. Chem., vol. 20, pp. 510-515, 1977; Iizuka et al. U.S. Pat. No. 4,711,958; and Hoover et al., EP published patent application 266,950).
Heretofore, 3S-amino-4-cyclohexyl-2R-hydroxybutyrate and 3S-amino-2R-hydroxy-5-methylhexanoate have been prepared by multistep, low yield syntheses from L-phenylalanine and L-leucine, respectively, involving wasteful co-production of extensive amounts of undesired 2S,3S-diastereoisomers, and the use of highly toxic cyanohydrin processes (Iizuka et al., loc. cit.; Rich et al., loc. cit.; Hoover et al., loc. cit.; Hoover, U.S. Pat. No. 4,599,198; Nashizawa et al., loc cit). In marked contrast, the present route, which begins with readily available L-malic acid (i.e., (R)-malic acid), is highly stereoselective, avoids the use of cyanohydrins and produces relatively high yields of the desired products.
The diethyl ester of present 2R-hydroxy-3S-(phenylmethyl)butanedioic acid, of the formula (II) below when R is C.sub.6 H.sub.5, was previously prepared from R)-malic acid via alkylation of diethyl (R)-malate (Seebach et al., Helv. Chim. Acta, vol. 63, pp. 197-200, 1980; cf. also Seebach et al., Org. Synth., vol. 63, pp. 109-120, 1984). Present use of the diisopropyl ester unexpectedly leads to higher overall yields while maintaining substantially the same stereoselectivity (i.e., about a 10:1 ratio of desired 2R,3S: undesired 2R,3R-diastereomer).
Since the completion of this invention, Gao and Sharpless [based on the text of J. Am. Chem. Soc., vol. 110, pp. 7378-9 (November, 1988), not the evidently erroneous stereodiagrams] appear to have described the synthesis of diisopropyl 2R-hydroxy-3S-(phenylmethyl)butandioate, of the formula (IX) below, from (+)diisopropyl 2R,3R-tartrate.